Osimertinib and Locally Ablative Radiotherapy in Patients With Synchronous Oligo-metastatic EGFR Mutant NSCLC (STEREO)

NCT04908956 | Terminated Phase 2 DMC

• 3 other identifiers: ETOP 17-202020-004114-35ESR-19-20384
• Study Type: interventional
• Target: 6
• Locations: 8 countries
• Sites: 18

Brief Summary

STEREO is single-arm phase II study, which aims to evaluate the safety and efficacy of osimertinib combined with early locally ablative radiotherapy of all cancer sites in patients with synchronous oligo-metastatic (primary tumour and maximum 5 metastases) EGFR-mutant (exon 19 deletion or exon 21 L858R) NSCLC. Eradication of all macroscopic cancer sites at the time of primary diagnosis by combined modality treatment is expected to decrease the risk of resistance development with only microscopic disease potentially remaining. This will result in an improvement of PFS and OS without added high-grade toxicity.

Conditions

NSCLC Stage IV; EGFR Gene Mutation

Keywords

NSCLC; EGFR mutation (exon 19 deletion and/or exon 21 L858R); Osimertinib; SBRT

Outcome Measures

Primary Outcomes (2)

• Safety of first-line EGFR-targeting osimertinib and SBRT to the primary tumour and all metastases

  Defined as the number of patients experiencing grade ≥2 pneumonitis, requiring medical treatment, any time during the first 18 months post enrolment over the total number of patients in the primary-endpoint safety cohort.

  Rate of grade ≥2 pneumonitis, requiring medical treatment, any time during the first 18 months on trial follow-up

• Efficacy of first-line EGFR-targeting osimertinib and SBRT to the primary tumour and all metastases

  If safety is proven, efficacy will be hierarchically tested in terms of Progression-free survival (PFS) according to RECIST v1.1, in the efficacy cohort. PFS is defined as the time from the date of enrolment until documented progression or death, if progression is not documented.

  Time from the date of enrolment until documented progression or death, if progression is not documented, assessed for a maximum of approx. 44 months after enrolment of the first patient

Secondary Outcomes (7)

• Overall survival (OS)

  Time from the date of enrolment until death from any cause. Censoring will occur at the last follow-up date, assessed for a maximum of approx. 44 months after enrolment of the first patient

• Pattern of disease progression

  Evaluated up to 18-months post enrolment

• Distant progression-free survival

  Time from date of enrolment until development of new metastases, excluding oligo-metastases diagnosed at enrolment - assessed for a maximum of approx. 44 months after enrolment of the first patient

• Objective response rate

  Time from enrolment across all trial assessment time-points - assessed for a maximum of approx. 44 months after enrolment of the first patient

• Duration of response

  From the date of first documentation of objective response to the date of first documented progression, relapse or death- assessed for a maximum of approx. 44 months after enrolment of the first patient

Study Arms (1)

Osimertinib & SBRT

EXPERIMENTAL

Osimertinib 80mg once daily p.o., until progression or unacceptable toxicity \& locally ablative radiotherapy (SBRT) to the primary tumour and to all metastatic sites.

Drug: Osimertinib; Radiation: Stereotactic Body Radiation Therapy (SBRT)

Interventions

Osimertinib DRUG

Osimertinib is a Tyrosine Kinase Inhibitor (TKI). It is an irreversible inhibitor of Epidermal Growth Factor Receptors (EGFRs) harboring sensitising-mutations (EGFRm) and TKI-resistance mutation T790M. The appropriate number of osimertinib tablets (80 mg or 40 mg if the dose is reduced due to toxicity) will be provided to patients to be self-administered at home.

Also known as: Tagrisso

Osimertinib & SBRT

Stereotactic Body Radiation Therapy (SBRT) RADIATION

SBRT will be delivered using risk-adapted SBRT with a maximum of 5 SBRT fractions.

Osimertinib & SBRT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed, treatment naïve EGFR-mutant NSCLC, with or without T790M resistance mutation. Presence of the sensitising EGFR-mutation (exon 19 deletion and/or exon 21 L858R) detected by an accredited laboratory.
• Synchronous oligo-metastatic stage IV disease (max 5 lesions)
• Measurable disease as defined according to RECIST v1.1
• All lesions amenable for radical radiotherapy according to local judgment
• Age ≥18 years
• ECOG performance status 0-2
• Life expectancy ≥12 months
• Adequate haematological, renal \& liver function
• Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test within 7 days before enrolment.
• Written IC for protocol treatment

You may not qualify if:

• Prior chemotherapy, immunotherapy, radiotherapy or therapeutical surgery for NSCLC (an exception is the resection and postoperative radiotherapy of the resection cavity of CNS or adrenal metastases)
• More than 5 distant oligo-metastases (any second intra-thoracic lesion will count as a distant metastasis; regional nodal metastases will not count towards 5 oligo-metastases) and more than 2 intra-thoracic lesions.
• Brain metastases not amenable for radiosurgery or neurosurgery
• Presence of leptomeningeal metastases
• Symptomatic spinal cord compression
• Extracranial metastatic locations not amenable for radical radiotherapy
• Currently receiving medications or herbal supplements known to be potent CYP3A4 inducers
• Any evidence of severe or uncontrolled systemic diseases
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib
• Any of the following cardiac criteria: QTcF \>470 msec; Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG; Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
• Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD
• Idiopathic pulmonary fibrosis which is a contraindication to lung radiation.
• History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
• Women who are pregnant or in the period of lactation.

Sponsors & Collaborators

• ETOP IBCSG Partners Foundation: lead
• AstraZeneca: collaborator

Study Sites (18)

IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)

Meldola, 47014, Italy

Location

Instituto Europeo di Oncologia (IEO)

Milan, Italy

Location

AULSS2 Marca Trevigiana Treviso

Treviso, Italy

Location

The Netherlands Cancer Institute Amsterdam

Amsterdam, 1006 BE, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Medical University Gdansk

Gdansk, Poland

Location

National University Hospital

Singapore, Singapore

Location

National Cancer Center

Goyang-si, 10408, South Korea

Location

Severance Hospital, Yonsei University Health System

Sinchŏn-dong, South Korea

Location

Hospital General de Alicante

Alicante, 03010, Spain

Location

Vall d'Hebron University Hospital

Barcelona, 08035, Spain

Location

Catalan Institute of Oncology, L'Hospitalet de Llobregat

Barcelona, Spain

Location

Centro Integral Oncologíco Clara Campal (CIOCC) HM Hospitales

Madrid, 28050, Spain

Location

Hospital Clínico de Valencia

Valencia, Spain

Location

Sahlgrenska University Hospital

Gothenburg, Sweden

Location

Karolinska Universitetssjukhuset Solna

Stockholm, 171 76, Sweden

Location

Kantonsspital Aarau

Aarau, Switzerland

Location

Universitätsspital Zürich USZ

Zurich, 8091, Switzerland

Location

Related Publications (7)

• Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18.

  PMID: 29151359 BACKGROUND

• Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; FLAURA Investigators. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. doi: 10.1056/NEJMoa1913662. Epub 2019 Nov 21.

  PMID: 31751012 BACKGROUND

• Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA Jr, Aisner DL, Gaspar LE, Kavanagh BD, Doebele RC, Camidge DR. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012 Dec;7(12):1807-1814. doi: 10.1097/JTO.0b013e3182745948.

  PMID: 23154552 BACKGROUND

• Wang X, Zeng M. First-line tyrosine kinase inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small cell lung cancer: Interim results of a randomized phase III, open-label clinical trial (SINDAS) (NCT02893332). Journal of Clinical Oncology 2020; 38(15_suppl): 9508-

  BACKGROUND

• Misale S, Fatherree JP, Cortez E, Li C, Bilton S, Timonina D, Myers DT, Lee D, Gomez-Caraballo M, Greenberg M, Nangia V, Greninger P, Egan RK, McClanaghan J, Stein GT, Murchie E, Zarrinkar PP, Janes MR, Li LS, Liu Y, Hata AN, Benes CH. KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition. Clin Cancer Res. 2019 Jan 15;25(2):796-807. doi: 10.1158/1078-0432.CCR-18-0368. Epub 2018 Oct 16.

  PMID: 30327306 BACKGROUND

• Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, Mulroy L, Lock M, Rodrigues GB, Yaremko BP, Schellenberg D, Ahmad B, Griffioen G, Senthi S, Swaminath A, Kopek N, Liu M, Moore K, Currie S, Bauman GS, Warner A, Senan S. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019 May 18;393(10185):2051-2058. doi: 10.1016/S0140-6736(18)32487-5. Epub 2019 Apr 11.

  PMID: 30982687 BACKGROUND

• Iyengar P, Wardak Z, Gerber DE, Tumati V, Ahn C, Hughes RS, Dowell JE, Cheedella N, Nedzi L, Westover KD, Pulipparacharuvil S, Choy H, Timmerman RD. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018 Jan 11;4(1):e173501. doi: 10.1001/jamaoncol.2017.3501. Epub 2018 Jan 11.

  PMID: 28973074 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

osimertinib; Radiosurgery

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Matthias Guckenberger, MD-PhD

  University Hospital, Zürich

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2021
• First Posted: June 1, 2021
• Study Start: August 4, 2022
• Primary Completion: October 31, 2023
• Study Completion: February 29, 2024
• Last Updated: June 28, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1); NL (2); CH (2); KR (2); SE (2); SG (1); IT (3); ES (5)